A new method was developed to measure cerebrovascular permeability to poorly permeable as well as rapidly permeable sustances. Pharmacokinetic principles for the central nervous system were established that demonstrate in rats that cerebrovascular permeability of nonelectrolytes and organic electrolytes is related linearly to the octanol/water partition coefficient. Synthetic opioid peptides are significantly permeable at the blood-brain barrier. In senescent rats, studies with 14C-sucrose show that cerebrovascular integrity is maintained, contrary to the immune hypothesis for brain aging. Barrier permeability can be increased by 10 to 20 fold, by infusing a hypertonic solution of arabinose or mannitol into the carotid artery of rats or dogs. The osmotic method transiently elevates brain water and regional brain glucose consumption, but does not produce long-term cerebral pathology. As a pharmacological tool, the osmotic method has been used to increase brain uptake of methotrexate (an anti-tumor agent) and exogenous enzymes (for use in enzyme replacement therapy). A theory of brain edema was presented to interpret brain water changes following increased barrier permeability, and provides a rational approach to treatment of edema.